Bcl6, Irf2, and Notch2 promote nonclassical monocyte development

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Ly6C^lo monocytes are crucial for vascular endothelium surveillance.
• Ly6C^lo monocytes are known to develop from Ly6C^hi monocytes.
• NOTCH2 signaling is implicated in Ly6C^lo monocyte development, but the underlying mechanisms are unclear.

Purpose of the Study:

• To investigate the role of NOTCH2 signaling in myeloid progenitors on Ly6C^lo monocyte development.
• To elucidate the transcriptional requirements for Ly6C^lo monocyte differentiation.

Main Methods:

• In vitro culture of myeloid progenitors.
• NOTCH2 signaling induction using delta-like ligand 1 (DLL1).
• Analysis of monocyte subset transition and gene expression (TREML4, BCL6, IRF2, NUR77).

Main Results:

• DLL1-induced NOTCH2 signaling promoted the transition of Ly6C^hi TREML4^- monocytes to Ly6C^lo TREML4⁺ monocytes.
• BCL6 deletion abrogated Ly6C^lo monocyte development.
• IRF2 was essential for Ly6C^lo monocyte development in a cell-intrinsic manner.
• DLL1-induced transition required IRF2 but not necessarily BCL6 or NUR77.

Conclusions:

• NOTCH2 signaling, via DLL1, drives Ly6C^lo monocyte development.
• IRF2 is a critical transcription factor for Ly6C^lo monocyte differentiation.
• A transcriptional hierarchy involving BCL6, IRF2, and NUR77 regulates Ly6C^lo monocyte development.